Laparoscopy is non‐inferior to open surgery for rectal cancer: A systematic review and meta‐analysis

Abstract Background Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. Aims We started this largest‐to‐date meta‐analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. Materials & Methods Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. Results Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3‐year and 5‐year local recurrence, disease‐free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. Conclusion Laparoscopy is non‐inferior to open surgery for rectal cancer with respect to oncological outcomes and long‐term survival. Moreover, laparoscopic surgery provides short‐term advantages, including faster recovery and less complications.


| INTRODUCTION
Colorectal cancer (CRC) is the third most common cause of cancer death in the United States with an incidence rate of 35.3 and mortality rate of 13.2 per 100,000 population.Approximately one-third of these cases are rectal cancers. 1,2The mainstay treatment for rectal cancer remains surgical resection.Considered as a major landmark, laparoscopic colectomy was first performed on 20 patients by Jacobs et al. 3 Over the next 30 years, the theory and technique of laparoscopic surgery in the management of rectal cancer have been standardized and improved enormously.Since 2006, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines had recommended laparoscopic-assisted colectomy to be the priority option for the qualified cases.However, the application of laparoscopy in rectal cancer is still controversial.
Laparoscopic surgery has unbeatable advantages in terms of postoperative recovery.The major controversies over laparoscopy versus open proctectomy are on the oncological outcomes and long-term survival.The early researches showed doubts on the high incidence of postoperative and peritoneal implantation metastasis after laparoscopic surgery. 4On the contrary, accumulating clinical trials had proved the safety and efficacy of laparoscopic proctectomy compared with open surgery.However, there had been no comprehensive assessment and comparison covering all the aspects of the two procedures in the treatment of rectal cancer, especially the pathological outcomes and long-term survival.Based on a comprehensively review of literature, we started this largest-to-date meta-analysis to make an overall comparison between the two surgical methods.

| METHODS AND METHODS
The protocol for this meta-analysis was available in PROSPERO (CRD42020211718).

| Literature search
We searched literatures involved with randomized controlled trials (RCTs) or nonrandomized controlled trials (NRCTs) on the following online databases: MEDLINE (through PubMed), Cochrane Library and Embase Databases, covering a period from January 1990 to March 2020.The search string was as follows: (rectal cancer or rectal carcinoma or rectal neoplasms) and (treatment or therapy or access or approach or management) and (laparoscopy or laparoscopic surgery) and (open surgery or laparotomy).Manual retrieval of relevant literature reference was available to expand the search and to ensure that no research was omitted.Only full-text English-language trials that met the selection criteria were retrieved and reviewed.

| Inclusion criteria
The trials were included based on the following inclusion criteria: (1) RCTs or NRCTs conducted in the period from January 1990 to March 2020; (2) the population of interest were adults diagnosed with rectal cancer by pathology of histology and underwent surgical treatment by means of laparoscopic proctectomy or open surgery; the surgical procedure of protectomy including anterior resection, abdominoperineal resection and intersphincteric resection was made according to the tumor localization above the anal verge, extent of tumor invasion and histologic type; (3) the selected literature must include two sets of data comparison of laparoscopic surgery group and open surgery group in the following aspects: surgical process, pathological results, postoperative recovery and short-term or long-term outcomes; and (4) literatures were full-text papers and published in English.

| Exclusion criteria
The trials were excluded based on the following exclusion criteria: (1) articles were not written in English, or unable to provide full text; (2) review, editorials and commentary articles; (3) literatures were published by the same researcher or research institutes; and (4) data provided by the paper were not clear and valid or could not be obtained via calculation.

| Quality assessment
The quality of trials was assessed independently by two authors (LI and XU) using two methods.All RCTs were assessed by the Cochrane risk of bias criteria, 5 whereas the NRCTs were assessed by the Newcastle-Ottawa Scale (NOS), 6 as recommended in the Cochrane Handbook.A score above 6 indicated high quality; otherwise, a lower score indicated poor quality.If controversy existed between the two independent evaluations, all of the authors participated in a discussion to resolve the issue.

| Study Selection
After the combined search, 1564 articles were identified.Titles and abstracts of these records were screened for inclusion.1323 articles were rejected and the remaining 241 articles then underwent full-text evaluation.Finally, 113 articles including 20 RCTs and 93 NRCTs met the inclusion criteria.The PRISMA flowchart for study inclusion and exclusion process was showed in Figure 1.Quality assessment of the included articles according to the Cochrane Collaboration's tool for assessing risk of bias for RCTs and to the NOS for prospective NRCTs were shown in Table 2 and Figure 2.

| Meta-analysis results
The specific data of the results of the meta-analysis comparing laparoscopic versus open surgery for rectal cancer in the aspects of intraoperative, pathological, postoperative and survival outcomes were listed in Table 3.  S2).
Only three studies reported 10-year LR and DR, four studies reported 10-year DFS and OS.No significant differences were showed based on these 10-year data of the two groups (data not shown).
Since laparoscopic surgery were applied to the resection of rectal cancer, numerous studies had been carried out to evaluate the surgical and oncological outcomes of this approach compared with traditional open surgery.Meanwhile, countless meta-analyses had drawn many conclusions based on the analysis of different types of trials.However, there had been no comprehensive assessment and comparison covering all the aspects of the two procedures in the treatment of rectal cancer, especially the pathological outcomes and long-term survival.We started T A B L E 1 (Continued)   this largest-to-date meta-analysis including 113 studies spanning over 30 years to fill the vacuum.In order to include as many patients as possible, not only RCTs but also numerous NRCTs from different medical centers were incorporated into our research, and conditions of inclusion criteria (different locations or stages of rectal cancer, with or without nCRT, different operation styles and studies with small sample size) was relaxed to a certain extent.The 93 NRCTs showed low risk of bias which left these reports convincing.Based on the overall investigation, the genuine effectiveness of laparoscopic proctectomy could be assessed accurately.The surgical approach for upper rectal cancer was equivalent to the sigmoid cancer, while the standard treatment for mid and low rectal cancer was TME.A successful resection of rectal cancer should meet the conditions of complete TME, a clear circumferential margin (CRM, ≥1 mm) and a clear distal resection margin (DRM, ≥1 mm). 29The standardization of TME improved the prognosis of rectal cancer by reducing the positive margin and local recurrence rates. 128This concept demands the sharp separation of the visceral fascia from the parietal plane.The resected specimen was the whole rectal tumor with an intact coverage including the main lymphatic drainage. 129It was evident that the magnified, illuminated images and pneumoperitoneum provided by laparoscopy facilitated the operation in the narrow pelvic space.In that case, a high-quality of resected specimen might be more easily to obtain.The results of this meta-analysis indicated that the 3year LR and 5-year LR were both significantly decreased after the laparoscopic surgery, and eventually lead to longer DFS and OS.Part of that improvement might be attributable to the radical resection of the tumor and mesorectum under direct vision created by laparoscopy.Although there was no significant difference of TME completeness and number of harvested lymph nodes found in laparoscopic surgery compared with open surgery, the positive rate of CMR and DMR were both reduced in the laparoscopy group.These results might contribute to the decreased LR.NCCN guidelines mentioned that some studies had shown that laparoscopy is associated with higher rates of CMR and incomplete TME, which was not supported by our large-scale metaanalysis.Moreover, there were no significant differences of 3-year DR and 5-year DR between the two groups.It suggested that laparoscopy might reduce the local recurrence without promoting distant metastasis.It should be noted that no significant difference of these survival indexes was found in the RCT subgroup.
The ultimate goal of treatment for cancer was not only an optimal oncological outcome, but also rapid recovery and improved quality of life.Our study revealed that patients could benefit from laparoscopic surgery in the postoperative recovery, including earlier return of bowel function, improved cosmesis and reduced pain owing to small incisions, earlier ambulation, shorter hospital stay and less complications.The total incidence of postoperative complications, morbidity of major complications and mortality within 30 days were all significantly decreased in the laparoscopy group without increased risk of reintervention.The fast recovery after surgery enabled patients to initiate following adjuvant therapy in a shorter period, which was a favorable factor contributing to the improvement of the prognosis.
The pneumoperitoneum created by laparoscopic surgery effectively expanded the activity of abdomen.However, the expansion of pelvic cavity was limited.Accomplishment of anastomosis under laparoscopy without collateral damage required precise manipulation of the surgeons.Only the well-trained doctors were qualified to perform laparoscopic rectal resection which could provide the equivalent oncologic outcomes and faster postoperative recovery.The COREAN trial was competed by seven highly skilled laparoscopic specialists, it suggested that better short-term outcome could be achieved in expert hands. 20Several researches recommended effective self-taught learning curve was about 50-80 laparoscopic rectal resections. 130The rates of conversion to laparotomy, operation time, blood loss and complications were all decreased in the cases performed by senior surgeons.Moreover, the natural orifice specimen extraction surgery and robotic-assisted laparoscopic surgery have been applied in the surgical treatment of cancer as technology evolved.These kinds of minimal invasive surgery demanding special surgical skills could further decrease the operative trauma and promote postoperative recovery.In that case, the role of surgeons in the surgery and the outcomes of patients was crucial.The experience of surgeons should be taken into consideration in the further strictly controlled trials.The laparoscopic surgery did require longer operative time, but time gap between the two approaches could be closing as the well-trained surgeons have perfected their surgical techniques.Drawbacks of laparoscopic protectomy will appear when it comes to specific cases, such as super obese patients or advanced tumor with extensive invasion.The difficulty of laparoscopy will lead to the conversion into open surgery.The range of conversion rate reported in the literatures mentioned in this paper was from 0% to 23.2%, and the average rate was 7.73%.The reasons for conversion might be as follows: too large tumors, lowlocated T4 tumors, previously irradiated pelvis, collateral damages of surgical operation and so on.The oncological outcomes of cases converted to open surgery is a controversial issue.Some studies showed similar outcomes, but others revealed worsen short-term outcomes, 131 higher rates of LR and reduced cumulative DFS. 132Most conversion in laparoscopic surgery are actually avoidable with adequate preoperative evaluation based on diagnostic imaging tests and a well-trained laparoscopic surgical team.The extended laparoscopic instruments also facilitate the operation on the obese patients.
T4 tumor is always the focus of controversy.It was identified as those that invade into other organs and structures and/or perforate the visceral peritoneum.All the guidelines suggest T4 rectal cancer as a contraindication for laparoscopic surgery, because the locally advanced tumor have a high risk of CMR or need en bloc resection of the adjacent infiltrated organs which might increase the convention rates and collateral increasing morbidity.Some studies have assessed the pathologic and oncologic results and suggested that laparoscopic surgery was feasible for T4 colorectal cancer. 108,124In this study, laparoscopic resection for all the stages of rectal cancer were merged and generally compared with open surgery.In that case, the analysis to some foci of controversy was ignored, such as T4 tumor, resection of primary tumor following nCRT and so on.Further stratified and grouped comparisons were urgently needed to compare the effect of these two surgical approaches in the specific population of rectal patients.Moreover, there were many more aspects in the recovery and prognosis of patients received surgical management deserves to be focused on and compared between the laparoscopy and open surgery, including the gender differences based on different anatomical structure, urinary and sexual dysfunction, incisional hernia, hospitalized cost and postoperative immunological changes.The robot-assisted laparoscopy has become emerging trend in the treatment of rectal cancer.The surgical outcomes of robotic surgery should also be compared with traditional laparoscopy and open surgery separately.
This article incorporated a large number of NRCTs which lead to a certain degree of bias in case selection and comparability.But they had already been accessed as high quality.Moreover, some NRCTs might have a preference in selection of population for specific purpose, such as elderly patients, T4 tumors, patients received nCRT and so on.These results were all unique and meaningful in the interpretation of the effect of laparoscopic proctectomy.As it should be, more large-scale RCTs and observational studies with stratified method, multivariable risk adjustment or propensity score analysis were urgently needed to evaluate the surgical outcomes of laparoscopy.
Bowel movement recovery was reported in 15 RCTs and 34 NRCTs.The weighted mean time before the first bowel movement or passing the first flatus was significantly shorter in laparoscopic surgery compared with open F I G U R E 1 Flow diagram of literature search and selection process.
The characteristics of the 113 studies were summarized in Table 1.It included 20 RCTs and 93 NRCTs for a total of 216,615 rectal cancer patients.Of them, 48,888 patients received laparoscopic proctectomy and 167,727 patients underwent open surgery.In the laparoscopic surgery group, patients required a conversion from laparoscopy to open surgery.The conversion cases remained in the laparoscopic surgery group according to the principle of intention-to-treat.
Quality assessment of the included non-randomized controlled studies based on the Newcastle-Ottawa Scale.
Note: Selections: 1, Representativeness of laparoscopic group (if yes, one point).2,Theopensurgery group was drawn from the same medical center (if yes, one point).3,Securerecord of ascertainment of exposure (surgical records, one point).4,Demonstrationthat outcome of interest was not present at start of study (if yes, one point).Comparability: 5, Group comparable for age, gender, and American Society of Anesthesiologists classification of physical status or Charlson's Comorbidity Index (if yes, one points; no point if one of these characteristics was not reported or if the two groups differed).6,Groupcomparable for neoadjuvant chemoradiotherapy, tumor location, stage, and surgical procedure (if yes, one points; no point if one of these characteristics was not reported or if the two groups differed).Outcome assessment: 7, Assessment of outcome (if independent blind assessment or record linkage, one point).8,Wasfollow-up long enough for outcomes to occur (if yes, one point).9,Adequacy of follow up of cohorts (if yes, one point; no points if follow-up not reported).Results of the meta-analysis comparing laparoscopic versus open surgery for rectal cancer.ORCIDLing Ma https://orcid.org/0000-0002-9562-5358Lei Ding https://orcid.org/0000-0001-7350-8508 F I G U R E 2The risk of bias assessment of included RCT studies.and editing (equal).Yu-bing Zhu: Data curation (equal); writing -original draft (equal); writing -review and editing (equal).Wen-xia Li: Formal analysis (equal); software (equal); writing -original draft (equal); writing -review and editing (equal).Kai-yu Xu: Formal analysis (equal).Ai-min Zhao: Project administration (equal); resources T A B L E 3 PRECIS Laparoscopy is non-inferior to open surgery for rectal cancer in intraoperative, pathological, postoperative and long-term outcomes.Laparoscopic surgery provides